ABSTRACT: Chronic fatigue syndrome (CFS)
or myalgic encephalomyelitis is a clinically defined syndromecharacterized by persistent or relapsing debilitating
fatigue for longer than 6 months in the absence of any definable medical
diagnosis. The cause of this syndrome is unknown. Symptoms of orthostatic
intolerance, such as disabling fatigue, dizziness, diminished concentration,
tremulousness, and nausea, are often found in patients with CFS. In this
review, we critically evaluate the relationship between orthostatic intolerance
and CFS. Particular emphasis is placed on clinical diagnosis, laboratory
testing, pathophysiology, and therapeutic management. It is hoped that
this review can provide a stimulus for further study of this complex and
disabling condition.

The symptom of fatigue is one of the most common
symptoms in clinical medicine, accounting for approximately 10 million
once visits per year in the United States. Fatigue can often be attributed
to underlying systemic illness (diabetes, cardiopulmonary disease, rheumatoid
arthritis) Fatigue also accompanies such psychiatric conditions as depression,
panic disorder, or somatization. Between 10 and 20% of patients visiting
their primary practitioners will have symptoms of fatigue of 6 months duration.
The etiology of this isolated fatigue or fatigue associated with other
minor illness symptoms remains undiagnosed and poorly treated. The term
fatigue can have several meanings, including exhaustion, a perceived decrease
in ability to perform mental or physical activity, a delay in recovery
after demanding physical activity, or the weariness of unrefreshing sleep.

Chronic Fatigue Syndrome: A Definition of the
Problem

Chronic fatigue syndrome (CFS), or myalgic encephalomyelitis,
is a clinically defined syndrome characterized by persistent or relapsing
debilitating fatigue for longer than 6 months in the absence of any definable
medical diagnosis. Not all agree on the specific criteria for the diagnosis
of this syndrome. All require the presence of substantial fatigue (50%
decrease in activity) for more than 6 months. There is less agreement as
to whether mental fatigue or cognitive impairment is an absolute requirement
for CFS and whether somatic complaints, such as muscle pain, multijoint
pain, headaches, postex-ertional malaise, unrefreshing sleep, adenopathy,
and sore throat, must accompany the condition. The most recent consensus
statement requires the presence of four of the eight complaints mentioned
for more than 6 months in addition to fatigue. The possibility of concomitant
psychiatric disorders, such as somatization or masked depression, is often
a confounding factor in the diagnosis of CFS.

In one study, the point prevalence of CFS was
estimated to range between 0.3 and 1%&rsquo and in another study, between
0.8 and 1.8%, according to the criteria applied for diagnosis. Whether
these data reflect community prevalence of CFS is unclear. In our experience
and the experience of others, women also seem to be affected by CFS three
to four times more frequently than men.In these people, the onset of illness
is often subacute. When assessed by the SF-36 health survey questionnaire,
patients with CFS exhibited diminished physical and mental health status,
even when compared with patients with heart disease, diabetes mellitus,
multiple sclerosis, and major depression. Moreover, the prognosis for complete
recovery of adults with CFS remains poor. Ultimately, although some dis
pute the existence of CFS as a valid diagnosis, we are left with the indisputable
fact that many young and previously productive people are disabled by a
condition that causes them to be absent from the work force

Orthostatic Intolerance: A Definition of the
Problem

Assuming an upright posture causes translocation
of approximately 800 ml of blood from the intrathoracic venous compartment
to veins of the buttocks, pelvis and legs. The normal compensatory cardiovascular
response to this orthostatic stress is a neurogenically mediated increase
in heart rate and in systemic vascular resistance. Not all vascular beds
contribute equally to the reflex increase in vascular resistance." Splanchnic
vasoconstriction accounts for one third of the increased vascular resistance
during normal levels of orthostatic stress. Skin and muscle vasoconstriction
accounts for approximately 40% of the increased vascular resistance during
normal levels of orthostatic stress and for an even higher percentage of
the total during very high levels of orthostatic stress. The fact that
syncope occurs if these compensatory reflexes are overwhelmed is well known.
Most also know that symptoms of orthostatic intolerance develop as these
reflexes approach the limit of compensation. Fewer appreciate the existence
of a significant patient cohort that chronically or frequently have these
symptoms to stressors that have minimal or no effect on asymptomatic subjects.
These patients predictably develop symptoms of disabling fatigue, dizziness,
diminished concentration, tremulousness, and nausea while standing. Simple
activities such as eating, showering, or low intensity exercise may profoundly
exacerbate these symptoms and may significantly impair even the most basic
activities of daily living

The true prevalence of orthostatic intolerance
is unknown; even rudimentary estimates are hard to obtain. These patients
complaints are often dismissed because of the nonspecific nature of the
symptoms reported. Other patients with orthostatic intolerance are incorrectly
diagnosed as having panic disorder or chronic anxiety. Moreover, the clinical
examination alone is often unrevealing because patients with orthostatic
intolerance do not have florid autonomic failure or orthostatic hypotension.
The recognition of the problem is further complicated by the fact that
mild and transient orthostatic intolerance may be observed in normally
asymptomatic subjects during mild hypovolemia, after prolonged bedrest,
and in some women during certain phases of the menstrual cycle.Orthostatic Intolerance in CFS

In 1987, Streeten noted symptoms of weakness and
fatigue in about one third of patients with or-thostatic intolerance. Moreover,
severe fatigue was the most prominent symptom observed in seven patients
who exhibited a delayed (after 10-30 minutes) fall in blood pressure while
standing. The pivotal report of Rowe et al has brought to the fore the
question of the relationship between orthostatic intolerance and CFS. In
this initial report, all seven adolescent patients tested with a protocol
of head-up tilt during intravenous infusion of the adrenergic agonist isoproteronol
developed clinically important hypotension and presyncope or syncope. Four
of these patients had apparent improvement of symptoms when treated with
atenolol or disopyramide. This reported therapeutic success has attracted
the attention of the many patients with CFS who, to date, have not had
effective medical treatment of their condition.

Delineation of the relationship between CFS and
orthostatic intolerance is important for several reasons. First, many of
the primary symptoms of ortho-static intolerance are often seen in patients
with disabling CFS. It is conceivable that patients with primary disorders
of orthostatic tolerance may be mislabeled as having CFS. Alternatively,
those with orthostatic intolerance may constitute one well-defined subgroup
of CFS. Second, insights derived from the pathogenesis of orthostatic intolerance
may provide valuable insights into CFS. Third, strategies that are effective
in the treatment of orthostatic intolerance may prove effective in the
treatment of CFS. Lastly, objective documentation of orthostatic intolerance
may aid patients with CFS who are attempting to prove that they are aflicted
with a valid medical illness. This review will attempt to address critically
the following questions: Is there a relationship between orthostatic intolerance
andg CFS? If so, can it be recognized clinically? What type of laboratory
evaluation should be carried out? Who should be evaluated? And, finally,
is the condition amenable to therapy? Are Patients with Orthostatic Intolerance
Clinically Recognizable( They are recognizable if appropriate attention
is paid to history and physical examination. Certain features of CFS bear
strong resemblance to those of the postural tachycardia syndrome (POTS).
More often than not, there is a history of subacute onset of symptoms,
often preceded by a viral prodrome. Women seem to be disproportionately
affected (almost 4:1). The age of presentation of POTS is similar to CFS
(between 15 and 50 years). Most patients have had symptoms for about 1
year when first evaluated; these symptoms may persist for several years.
The symptoms that are most helpful include exacerbation of primary symptoms
(fatigue, lightheadedness, or diminished during upright posture, heat stress,
or after exercise. Some may also complain of urinary frequency, diarrhea
or constipation, or early satiety. We consider the abrupt onset of symptoms
to be an important clinical feature. We have occasionally seen patients
with a history of mild orthostatic intolerance&ldquo that clearly preceded
the onset of CFS. This mild orthostatic intolerance may be found in many
normal healthy individuals. Interestingly, these patients may report that
tilt-table testing mimicked their symptoms of occasional lightheadedness
but not the primary symptoms of CFS. The signs that are most helpful include
the presence of livedo reticularis or acral vasoconstriction, collapse
of pulse pressure during rapid standing, and exaggerated postural tachycardia
or large swings in heart rate or pulse pressure during stand. It is important
to realize that patients often have good or bad periods of several days
duration; hence, clinical signs may fluctuate. If an appropriate history
is obtained but signs are lacking, we suggest that the patient be reevaluated
clinically.

What Is the Prevalence of Orthostatic Intolerance
in CFS? There are few data concerning the prevalence of orthostatic intolerance
in CFS; all data obtained suffer from the limitation of referral bias of
academic centers. Data from the group at Johns Hopkins suggest that virtually
all subjects (22 of 23) with CFS have many of their primary symptoms reproduced
during head-up tilt. In contrast, others who attempted to specifically
recruit subjects with CFS who reported symptoms of orthostatic intolerance
found that only 25% (4 of 16) of patients had syncope or presyncope during
head-up tilt. In another study, 40% (30 of 75) of unselected patients with
CFS had clinical and laboratory evidence of orthostatic intolerance. Another
study suggested that 28% (22/78) of patients had abnormal responses to
head-upLaboratory Evaluation of Orthostatic Intolerance
in CFS The Controversy. The methodology of the laboratory evaluation of
patients with CFS goes to the heart of the definition of orthostatic intolerance.
In its strictest definition, orthostatic intolerance reflects the inability
to maintain consciousness in the upright position. Those who define orthostatic
intolerance as the inability to maintain postural normo-tension in the
face of a normal gravitational stress test patients with 40-60 minutes
of head-up tilt alone. If syncope does not result and an appropriate hemodynamic
response is observed, then the patient cannot be deemed to be orthostatically
intolerant. This physiological approach is the one that we advocate. All
of the studies that report abnormal response in the range of 25-40% have
used this approach.The Johns Hopkins group suggest that head-up tilt be
combined with isoproteronol. This necessitates a quasi-fasting state and
insertion of an intravenous catheter during testing. A standard head-up
tilt is performed; if negative, it is repeated during isoproteronol infusion.
The use of isoproteronol as a provocative agent for inducing syncope is
well-established. The rationale for its use stems from the view that neurally
mediated syncope is triggered reflexively by input from unmyelinated vagal
cardiac ventricular afferents and is activated by maneuvers that impair
cardiac filling or that increase cardiac contractility.This hypothesis
has been seriously questioned by many investigators. Moreover, isoproteronol
and invasive instrumentation have the added disadvantage of provoking syncope
in many healthy young subjects and in provoking panic attacks in those
prone to anxiety. The limitations of isoproteronol may perhaps be overlooked,
given the need to diagnose the cause(s) of unexplained syncope.&ldquo
In our opinion, the use of isoproteronol is less defensible if it is required
to demonstrate orthostatic intolerance. Lastly, although we assume that
the chronic symptoms of orthostatic intolerance are the equivalent of those
of impending syncope (fatigue, malaise), there is no evidence that mechanisms
that trigger syncope are continuously operant in the production of the
symptoms of orthostatic intolerance.

Laboratory Evaluation of Orthostatic Intolerance
in CFS?

What Is an Abnormal Response? Widespread severe
autonomic failure has not been observed in CFS. Although neurally mediated
syncope may be observed in normal subjects during head-up tilt," in our
experience, many normal subjects do not experience the prolonged prodrome
of malaise and lightheadedness that patients with orthostatic intolerance
do. Moreover, the syncopal response to head-up tilt in those with true
orthostatic intolerance is highly reproducible over time. The criteria
used to diagnose postural tachycardia is a sustained heart rate increase
of greater than 30 beats/minute if a short duration (5-10 minutes) head-up
tilt is used. A rise of 30 beats/minute during prolonged head-up tilt has
been defined as abnormal in some studies, but this value is often noted
in young subjects near the end of the tilt duration. To discriminate between
milder forms of orthostatic intolerance and POTS, some have suggested the
criterion of a rise in heart rate to greater than 120 beats/minute in addition
to an increase of 30 According to this definition, approximately 25-40%
ofthe patients with CFS and orthostatic intolerance that we have tested
would have POTS. Lastly, it is important to realize that many patients
with CFS may be taking medications (eg, antidepressants) that treat symptoms
empirically but may interfere with autonomic testing. We advocate discontinuing
all such medications for at least five half-lives and, if possible, for
a minimum of 1 month before testing to be able to unequivocally document
orthostatic intolerance if it exists.

Pathophysiology of Orthostatic Intolerance
in CFS.

The different patterns of postural tachycardia
and neurally mediated syncope suggest that there is no unique abnormality
underlying orthostatic intolerance and CFS. A detailed discussion of the
current theories concerning the pathogenesis of POTS and neurally mediated
syncope is beyond the scope of this review and the reader is referred elsewhere
for discussion of these issues. As a general principle, it can be said
that the exaggerated tachycardia and vasoconstriction of POTS compensates
for chronic conditions that promote central hypovolemia (depleted intravascular
volume, exaggerated venous pooling), whereas impaired vasoconstrictor function
is often seen in neurally mediated syncope. Minor abnormalities of cardiovascular
autonomic function tests have been noted in some studies but there is no
evidence of widespread pandysautonomia in these patients. As noted above,
the acuity of onset of symptoms in many patients is reminiscent of POTS
and may suggest that CFS is in some cases an attenuated form of pandysautonomia.
We are unaware of any studies that systematically test other autonomic
effectors in patients with orthostatic intolerance and CFS, but data of
this kind would be very useful in determining whether some of these patients
have an attenuated form of generalized dysautonomia.

Is the reduced orthostatic tolerance of some patients
with CFS simply the result of cardiovascular deconditioning? The two models
of cardiovascular deconditioning for which data are available are prolonged
bedrest or the zero-gravity conditions of prolonged space flight. Both
are associated with significant reductions in orthostatic tolerance, postural
tachycardia, or syncope. The postulated patho-geneses include compensatory
hypovolemia caused by the initial central translocation of intravascular
volume, decreased baroreflex responsveness, and increased leg and venous
compliance. None of these mechanisms is universally agreed upon; some researchers
have been unable to document changes in venous compliance or capillary
filtration, baroreflex responsiveness, or autonomic function seen by others.
A recent report has raised the intriguing suggestion that prolonged bedrest
leads to a smaller, less distensible left ventricle that operates on a
more compliant portion of the Starling curve, ultimately causing a reduction
in upright stroke volume and in orthostatic tolerance. Ultimately, although
bedrest might provide insights into the underlying pathophysiology of decondition-ing,
it is important to realize that the effect of diminished physical activity
on orthostatic tolerance has not been shown to be equivalent to the effect
of prolonged bedrest.Although deconditioning undoubtedly contributes to
the orthostatic intolerance in CFS, in our opinion, it cannot fully account
for the magnitude of the problem. Freeman et al found that deconditioning
accounted for some but not all of the laboratory abnormalities commonly
associated with orthostatic intolerance. Schondorf et al found that the
duration of symptoms of patients with CFS and orthostatic intolerance was
significantly less than that of patients with CFS without orthostatic intolerance.If
chronic deconditioning is the primary contributor to orthostatic intolerance,
then those with longer symptom duration would be more affected. The possibility
that there is a spectrum of susceptibility to the cardiovascular effects
of deconditioning can also not be ruled out at the present time. Although
some have suggested that this may depend on physical factors, such as body
habitus, there does not seem to be a significant difference in body habitus
between those who are orthostatically intolerant and those who are not.

Treatment of Orthostatic Intolerance in CFS.

Because many patients with orthostatic intolerance
are severely limited in their activities of daily life, it is obviously
important to identify and test strategies that might improve orthostatic
tolerance. It is reasonable to suppose that maneuvers that supplement arterial
and venous adrenergic activity or that increase plasma volume would significantly
improve orthostatic tolerance. Some of these modifications may occur after
a program of moderate exercise.&rdquo Although patients with CFS are
limited by the discomfort of an increased perception of exertion, there
are some data to support the notion that an appropriately designed exercise
program is beneficial.This benefit may not be related to improved orthostatic
tolerance; supine exercise normalized aerobic fitness and blood volume
but had no effect on orthostatic tolerance.Volume repletion by increasing
sodium intake or by treatment with fludrocortisone may theoretically improve
orthostatic tolerance by replenishing intra-vascular volume. The efficacy
of treatment may be limited by the aldosterone escape and by a diminution
in baseline sympathetic activity that is also observed even when no increase
in plasma volume is observed. Those who elect to try fludrocortisone must
be aware that many of the symptoms of sympathetic overactivity are enhanced
by fludrocortisone and many have severe headaches as a result of treatment.
The therapeutic effect of chronic administration of adrenergic analogs
may also be limited by compensatory reductions in sympathetic activity
and plasma volume. We suggest that any pharmacological treatment be tailored
to the physiological abnormalities observed and be implemented only in
conjunction with a program of gradual reconditioning. We stress patient
education concerning avoidance of stressors that may exacerbate orthostatic
intolerance. Physical counter-maneuvers are also employed to improve orthostatic
tolerance. In our opinion, any therapeutic options should be the subject
of blinded, placebocontrolled trials involving several centers with an
interest in treatment of CFS and orthostatic intolerance.